Hypertension is an inherited polygenic disease, and its expression modified by the environment. Molecular genetic techniques provide the opportunity for dissecting the genes responsible hypertension, but only one locus has been shown, definitively to cosegregate with high blood pressure humans. Major limitations in human studies include: l) small numbers of ascertained patients, 2) etiological heterogeneity (different genes in different patients), 3) technical and theoretical issues concerning a total genome scan using affected sibpairs. Consequently, genetic dissection in human has been limited to candidate genes. In contrast, the rat genetic models of hypertension are more tractable for genetic dissection and several loci which cosegregate with high blood pressure identified. Unfortunately, these studies used small crosses, focused on one locus at a time and did not control for genetic background effects. We propose to use four large crosses, controlled for genetic background effects, to determine genetically """"""""hot"""""""" loci to be studied in our patient populations. This approach reduces the number of genotypes to be done by our Human Genotyping Center and provides candidate regions, demonstrated to play a role in genetic susceptibility to hypertension. Identification of the """"""""hypertensive"""""""" genes is likely to involve positional cloning and physiological characterization, neither of which are likely to be accomplished in human. To facilitate the detection of genetic """"""""hot"""""""" spots and to facilitate the rapid transition from rat to human, we propose to: 1. Locate genetically """"""""hypertensive"""""""" loci using several large rat crosses. The best candidate genes are likely to be those identified in several crosses. Furthermore minimizing genetic background affects should increase our chance of identifying loci that act as modifiers and control expression of hypertension in humans. This strategy is analogous to that accomplished for type 1 diabetes [1]. 2. Convert regions of interest in the rat to human homologs. Conservation of gene order and use of radiation hybrids will facilitate the quick transition to genetic markers for genotyping in humans. 3. Map candidate genes in the human and in the rat. Only a limited number of candidate genes have been mapped in the rat, human or both. The localization of a candidate gene serves as a starting point, and if correct will obviate the need for positional cloning. 4. Identify the genes responsible for hypertension. Another goal of this RFA is to identify these genes. Our genetic network are focused on the genetic localization, we will however initiate the identification by constructing congenic lines of rats. Congenic rats will facilitate postional cloning, physiological characterization and studies on environmental interaction.
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